WARNINGS

In a few patients hydralazine may produce a clinical picture simulating systemic lupus erythematosus including glomerulonephritis. In
such patients hydralazine should be discontinued unless the benefit-to-risk determination requires continued antihypertensive therapy
with this drug. Symptoms and signs usually regress when the drug is discontinued but residua have been detected many years later.
Long-term treatment with steroids may be necessary. (See PRECAUTIONS, Laboratory Tests.)

PRECAUTIONS

General

Myocardial stimulation produced by Apresoline (hydralazine) can cause anginal attacks and ECG changes of myocardial ischemia. The drug has
been implicated in the production of myocardial infarction. It must, therefore, be used with caution in patients with suspected coronary
artery disease.

The “hyperdynamic" circulation caused by Apresoline (hydralazine) may accentuate specific cardiovascular inadequacies. For example,
Apresoline (hydralazine) may increase pulmonary artery pressure in patients with mitral valvular disease. The drug may reduce the pressor
responses to epinephrine. Postural hypotension may result from Apresoline (hydralazine) but is less common than with ganglionic blocking agents.
It should be used with caution in patients with cerebral vascular accidents.

In hypertensive patients with normal kidneys who are treated with Apresoline (hydralazine) , there is evidence of increased renal blood flow and
a maintenance of glomerular filtration rate. In some instances where control values were below normal, improved renal function has
been noted after administration of Apresoline (hydralazine) . However, as with any antihypertensive agent, Apresoline (hydralazine) should be used with caution
in patients with advanced renal damage.

Peripheral neuritis, evidenced by paresthesia, numbness, and tingling, has been observed. Published evidence suggests an
antipyridoxine effect, and that pyridoxine should be added to the regimen if symptoms develop.
The Apresoline (hydralazine) tablets (100 mg) contain FD&C Yellow No. 5 (tartrazine), which may cause allergic-type reactions (including
bronchial asthma) in certain susceptible individuals. Although the overall incidence of FD&C Yellow No. 5 (tartrazine) sensitivity in the general population is low, it is frequently seen in patients who are also hypersensitive to aspirin.

Information for Patients

Patients should be informed of possible side effects and advised to take the medication regularly and continuously as directed.

Laboratory Tests

Complete blood counts and antinuclear antibody titer determinations are indicated before and periodically during prolonged therapy with hydralazine even though the patient is asymptomatic. These studies are also indicated if the patient develops arthralgia, fever, chest pain, continued malaise, or other unexplained signs or symptoms.

A positive antinuclear antibody titer requires that the physician carefully weigh the implications of the test results against the benefits to be derived from antihypertensive therapy with hydralazine.

MAO inhibitors should be used with caution in patients receiving hydralazine.

When other potent parental antihypertensive drugs, such as diazoxide, are used in combination with hydralazine, patients should be continuously observed for several hours for any excessive fall in blood pressure. Profound hypotensive episodes may occur when diazoxide infection and Apresoline (hydralazine) are used concomitantly.

Drug/Food Interactions

Administration of hydralazine with food results in higher plasma levels.

Carcinogenesis, Mutagenesis, Impairment of Fertility

In a lifetime study in Swiss albino mice, there was a statistically significant increase in the incidence of lung tumors (adenomas and adenocarcinomas) of both male and female mice given hydralazine continuously in their drinking water at a dosage of about 250 mg/kg per day (about 80 times the maximum recommended human dose). In a P-year carcinogenicity study of rats given hydralazine by lavage at dose levels of 15, 30, and 60 mg/kg/day (approximately 5 to 20 times the recommended human daily dosage), microscopic examination of the liver revealed a small, but statistically significant, increase in benignneoplastic nodules in male and female rats from the high-dose group and in female rats from the intermediate-dose group. Benign interstitial cell tumors of the testes were also significantly increased in male rats from the high-dose group. The tumors observed are common in aged rats and a significantly increased incidence was not observed until 18 months of treatment. Hydralazine was shown to be mutagenic in bacterial systems (Gene Mutation and DNA Repair) and in one of two rat and one rabbit hepatocyte in vitroDNA repair studies. Additional in vim and in vitro studies using lymphoma cells, germinal cells, and fibroblasts from mice, bone marrow cells from Chinese hamsters and fibroblasts from human cell lines did not demonstrate any mutagenic potential for hydralazine.

The extent to which these findings indicate a risk to man is uncertain. While long-term clinical observation has not suggested that human cancer is associated with hydralazine use, epidemiologic studies have so far been insufficient to arrive at any conclusions.

Pregnancy Category C

Animal studies indicate that hydralazine is teratogenic in mice at 20 to 30 times the maximum daily human dose of 200 to 300 mg and possibly in rabbits at 10 to 15 times the maximum daily human dose, but that it is nonteratogenic in rats. Teratogenic effects observed were cleft palate and malformations of facial and cranial bones.

There are no adequate and well-controlled studies in pregnant women. Although clinical experience does not include any positive evidence of adverse effects on the human fetus, hydralazine should be used during pregnancy only if the expected benefit justifies the potential risk to the fetus.

Nursing Mothers

Hydralazine has been shown to be excreted in breast milk.

Pediatric Use

Safety and effectiveness in pediatric patients have not been established in controlled clinical trials, although there is experience
with the use of Apresoline (hydralazine) in these patients. The usual recommended oral starting dosage is 0.75 mg/kg of body weight daily in four
divided doses. Dosage may be increased gradually over the next 3-4 weeks to a maximum of 7.5 mg/kg or 200 mg daily.

Last reviewed on RxList: 12/8/2004
This monograph has been modified to include the generic and brand name in many instances.